Hemolysis in the spleen drives erythrocyte turnover

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DOI

  • T. R.L. Klei, University of Amsterdam, Sanquin Blood Supply Foundation
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  • J. Dalimot, University of Amsterdam
  • ,
  • B. Nota, Sanquin Blood Supply Foundation
  • ,
  • M. Veldthuis, Sanquin Blood Supply Foundation
  • ,
  • F. P.J. Mul, Sanquin Blood Supply Foundation
  • ,
  • T. Rademakers, University of Amsterdam
  • ,
  • M. Hoogenboezem, Sanquin Blood Supply Foundation
  • ,
  • S. Q. Nagelkerke, University of Amsterdam
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  • W. F.J. van IJcken, Erasmus University Rotterdam
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  • E. Oole, Erasmus University Rotterdam
  • ,
  • P. Svendsen
  • S. K. Moestrup
  • F. P.J. van Alphen, Sanquin Blood Supply Foundation
  • ,
  • A. B. Meijer, Sanquin Blood Supply Foundation, University of Amsterdam, Utrecht University
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  • T. W. Kuijpers, University of Amsterdam, Vrije Universiteit Amsterdam
  • ,
  • R. van Zwieten, University of Amsterdam, Sanquin Blood Supply Foundation
  • ,
  • R. van Bruggen, University of Amsterdam

Red pulp macrophages (RPMs) of the spleen mediate turnover of billions of senescent erythrocytes per day. However, the molecular mechanisms involved in sequestration of senescent erythrocytes, their recognition, and their subsequent degradation by RPMs remain unclear. In this study, we provide evidence that the splenic environment is of substantial importance in facilitating erythrocyte turnover through induction of hemolysis. Upon isolating human spleen RPMs, we noted a substantial lack of macrophages that were in the process of phagocytosing intact erythrocytes. Detailed characterization of erythrocyte and macrophage subpopulations from human spleen tissue led to the identification of erythrocytes that are devoid of hemoglobin, so-called erythrocyte ghosts. By using in vivo imaging and transfusion experiments, we further confirmed that senescent erythrocytes that are retained in the spleen are subject to hemolysis. In addition, we showed that erythrocyte adhesion molecules, which are specifically activated on aged erythrocytes, cause senescent erythrocytes to interact with extracellular matrix proteins that are exposed within the splenic architecture. Such adhesion molecule-driven retention of senescent erythrocytes under low shear conditions was found to result in steady shrinkage of the cell and ultimately resulted in hemolysis. In contrast to intact senescent erythrocytes, the remnant erythrocyte ghost shells were prone to recognition and breakdown by RPMs. These data identify hemolysis as a key event in the turnover of senescent erythrocytes, which alters our current understanding of how erythrocyte degradation is regulated.

Original languageEnglish
JournalBlood
Volume136
Issue14
Pages (from-to)1579-1589
Number of pages11
ISSN0006-4971
DOIs
Publication statusPublished - Oct 2020

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